1. Field of the Invention
The invention relates to a method of treating eyelid dermatitis.
2. Background Art
Eyelid dermatitis is characterized by eyelid skin which is inflamed, scaly, weeping, erythematous and/or pruritic; often this condition extends to other parts of the periorbital area, particularly under the eye. While the causes of this condition are various, including psoriasis, seborrhea, rosacea, contact urticaria, atopic dermatitis and contact dermatitis, treatment of eyelid dermatitis can be problematic because the eyelid and other periorbital skin is naturally thin and moist. Eyelid skin is, moreover, occluded because it retracts when the lid is open. Anti-inflammatory corticosteroids are generally known to cause skin atrophy, making their use especially contraindicated in thin-skinned areas.
Topical or other local application of potent glucocorticoids can produce severe toxic effects such as Cushingoid features, pituitary-adrenal suppression, skin atrophy, immunosuppression, weight gain and inhibition of wound healing. Other kinds of toxic responses, including allergies and cataracts, have resulted from long term use of drugs of this type.
Ophthalmic application of glucocorticosteroids presents additional problems. The protective mechanisms built into the eye allow only small amounts of doses applied to the eye to reach the target sites within the eye; generally, over 90 percent of the total dose will find its way into the general circulation. This in turn leads to serious systemic side effects of the type described above. Moreover, there is a more serious and specific side effect when these drugs are used in the eye, which is an increase in intraocular pressure (IOP). Corticosteroid-induced chronic or acute glaucoma has in fact been reported since the early 1960's. Generally, the corticosteroid is needed only topically to control the inflammation. However, the absorbed steroid is responsible for the serious side effects noted above. It is believed that the effect of the corticosteroid on the aqueous outflow pathway and adjacent tissue glycosaminoglycans (GAG's) is important in the development of glucocorticoid-induced ocular hypertension. Because of their tendency to elevate ocular pressure and to cause cataracts, the FDA has generally forbidden use of topical anti-inflammatory corticosteroids on the eyelid or periorbital skin and even facial skin in general.
The natural glucocorticosteroids and many of their marketed derivatives are Δ4 and Δ1,4 pregnenes having 21-hydroxy substituents. There are, however, a number of anti-inflammatory Δ4 and Δ1,4 androstenes described in the literature; note, for example, British Patent Specification No. 1,384,372; Phillipps et al. U.S. Pat. No. 3,828,080 and Kalvoda et al. U.S. Pat. No. 4,285,937.
In recent years, soft steroids have been developed in an effort to provide compounds having potent anti-inflammatory activity with minimal systemic activity. One series of soft steroids which is described as having potent anti-inflammatory activity with minimal systemic activity consists of the 17α-carbonates of Bodor U.S. Pat. No. 4,996,335. These compounds include as preferred embodiments haloalkyl 17α-alkoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylates and the corresponding Δ1,4 compounds, optionally bearing 6α- and/or 9α-fluorine and 16α- or 16β-methyl substituents. One of these compounds is chloromethyl 17α-ethoxycarbonyloxy-11β-hydroxyandrosta-1,4-dien-3-one-17β-carboxylate, also known as loteprednol etabonate. Loteprednol etabonate is presently marketed in the United States by Bausch & Lomb Pharmaceuticals, Inc. as Alrex® and Lotemax® and combined with tobramycin as Zylet® for ophthalmic use. Other uses of loteprednol etabonate are currently or have been in clinical trials (for rhinitis and various dermatological conditions).
Loteprednol etabonate has an impressive safety profile for its FDA-approved ophthalmic uses. It has now been marketed in the US for thirteen years, with approximately three million prescriptions written, for a variety of FDA-approved ophthalmic indications, including allergic conjunctivitis, general inflammatory conjunctivitis, post cataract surgery inflammation and uveitis.